Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface

Masubuchi, Nami; Araki, Marito; Yang, Yinjie; Hayashi, Erina; Imai, Misa; Edahiro, Yoko; Hironaka, Yumi; Mizukami, Yuya; Kihara, Yoshihiko; Takei, Hiraku; Nudejima, Mai; Koike, Masato; Ohsaka, Akimichi; Komatsu, Norio

doi:10.1038/s41375-019-0564-z

Cited by 40 publications

(74 citation statements)

References 19 publications

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“…Mutant CALR‐bound MPL largely presents immature N‐glycan 11,15 ; and an asparagine residue at 117, located in the extracellular domain of MPL, is required for the binding of mutant CALR and subsequent activation by it 11,16 . In agreement with these observations, mislocalization of mutant CALR outside the secretory pathway, due to deletion of SP, was seen to result in a loss of MPL binding and transformation capacity 15,17 . These findings implied that the first interaction between mutant CALR and MPL occurs in the ER, where MPL harbors immature N‐glycan.…”

Section: Engagement Of Mutant Calr and Mpl In The Secretory Pathwaymentioning

confidence: 53%

“…As a glycoprotein, MPL is believed to be a substrate of WT CALR in the ER (Figure 2), which raises the possibility that the process of initial engagement between mutant CALR and MPL would resemble the one with WT CALR, recognizing the substrate as a molecular chaperone. This hypothesis has been supported by the following experimental results: the oligosaccharide binding capacity of mutant CALR was found to be indispensable for MPL binding and activation 11,15,16 . Mutant CALR‐bound MPL largely presents immature N‐glycan 11,15 ; and an asparagine residue at 117, located in the extracellular domain of MPL, is required for the binding of mutant CALR and subsequent activation by it 11,16 .…”

Section: Engagement Of Mutant Calr and Mpl In The Secretory Pathwaymentioning

confidence: 75%

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Mechanism underlying the development of myeloproliferative neoplasms through mutant calreticulin

2020

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Deregulation of cytokine signaling is frequently associated with various pathological conditions, including malignancies. In patients with myeloproliferative neoplasms (MPNs), recurrent somatic mutations in the calreticulin (CALR) gene, which encodes a molecular chaperone that resides in the endoplasmic reticulum, have been reported. Studies have defined mutant CALR as an oncogene promoting the development of MPN, and deciphered a novel molecular mechanism by which mutant CALR constitutively activates thrombopoietin receptor MPL and its downstream molecules to induce cellular transformation. The mechanism of interaction and activation of MPL by mutant CALR is unique, not only due to the latter forming a homomultimeric complex through a novel mutant‐specific sequence generated by frameshift mutation, but also for its ability to interact with immature asparagine‐linked glycan for eventual engagement with immature MPL in the endoplasmic reticulum. The complex formed between mutant CALR and MPL is then transported to the cell surface, where it induces constitutive activation of downstream kinase JAK2 bound to MPL. Refined structural and cell biological studies can provide an in‐depth understanding of this unusual mechanism of receptor activation by a mutant molecular chaperone. Mutant CALR is also involved in modulation of the immune response, transcription, and intracellular homeostasis, which could contribute to the development of MPN. In the present article, we comprehensively review the current understanding of the underlying molecular mechanisms for mutant molecular chaperone‐induced cellular transformation.

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Section: Engagement Of Mutant Calr and Mpl In The Secretory Pathwaymentioning

confidence: 53%

Section: Engagement Of Mutant Calr and Mpl In The Secretory Pathwaymentioning

confidence: 75%

Mechanism underlying the development of myeloproliferative neoplasms through mutant calreticulin

2020

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“…It enters a secretary pathway and is primarily localized in the Golgi apparatus and further traffics to the cell membrane [69,76,77,79]. Cell surface localization of MPL-CALR complex has been detected and is shown to be essential for the oncogenic activity [76,77]. Also, the N-terminal ER signal peptide is required for the oncogenic function of mutant calreticulin too, suggesting that the MPL-CALR interaction is initiated in the ER [76] (Fig.…”

Section: Calr Mutationmentioning

confidence: 98%

“…Firstly, the binding and activation of MPL by mutant calreticulin require its N-glycan binding domain, as glycan-deficient CALR del52 is unable to activate JAK-STAT pathway [69]. Several studies also show that this protein-protein interaction could not be maintained when certain amino acid residues at this domain is mutated [75][76][77]. Secondly, mutant calreticulin has been shown to undergo homomultimerization through its mutant specific C-terminus and they interact with MPL as multimers [78].…”

Section: Calr Mutationmentioning

confidence: 99%

“…Mutant calreticulin loses its ER retention signal due to the mutation at the C-terminus. It enters a secretary pathway and is primarily localized in the Golgi apparatus and further traffics to the cell membrane [69,76,77,79]. Cell surface localization of MPL-CALR complex has been detected and is shown to be essential for the oncogenic activity [76,77].…”

Section: Calr Mutationmentioning

confidence: 99%

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Progress in elucidation of molecular pathophysiology of myeloproliferative neoplasms and its application to therapeutic decisions

Jia

Královics

2019

Int J Hematol

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Myeloproliferative neoplasms (MPNs) are hematological diseases that are driven by somatic mutations in hematopoietic stem and progenitor cells. These mutations include JAK2, CALR and MPL mutations as the main disease drivers, mutations driving clonal expansion, and mutations that contribute to progression of chronic MPNs to myelodysplasia and acute leukemia. JAK-STAT pathway has played a central role in the disease pathogenesis of MPNs. Mutant JAK2, CALR or MPL constitutively activates JAK-STAT pathway independent of the cytokine regulation. Symptomatic management is the primary goal of MPN therapy in ET and low-risk PV patients. JAK2 inhibitors and interferon-α are the established therapies in MF and high-risk PV patients.

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Impact of Calreticulin and Its Mutants on Endoplasmic Reticulum Function in Health and Disease

Arshad

Cresswell

2021

Cellular Biology of the Endoplasmic Reticulum

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Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface

Cited by 40 publications

References 19 publications

Mechanism underlying the development of myeloproliferative neoplasms through mutant calreticulin

Mechanism underlying the development of myeloproliferative neoplasms through mutant calreticulin

Progress in elucidation of molecular pathophysiology of myeloproliferative neoplasms and its application to therapeutic decisions

Impact of Calreticulin and Its Mutants on Endoplasmic Reticulum Function in Health and Disease

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